Preparation of steroid 21-aldehydes



. 1 1,113,011 PREPARATION OFVSTEROID ZI-ALDEHYDES John P. Conbere, Fanwood, N. J., assignor to Merck &

Co., Inc., Rahway, N. J., a corporation of New Jersey NoDrawing. Application June 16, 1953,

' Serial No. 362,135

6 Claims. c1. 260-39745) This invention relates to steroid aldehydes. More part1cularly, it is concerned with steroids having a glyoxyl side chain at the 17 position and processes for producing such compounds.

The 17-glyoxyl steroids-are useful intermediates in the preparation of other valuable steroid compounds. Furthermore 17-glyoxy1 steroids such as A 3,11,20 triketo 2,113,011 Patented Dec. 4,

"ice

. a 2 1 by reacting a 17-glyoxyl steroid with a suitable alcohol such as methanol, ethanol, or propanol. When a mercaptan is used inplace of an alcohol, the corresponding hemimercaptal or mencaptal may be readily produced. Furthermore, by reacting an aliphatic acid anhydride with a 17-glyoxyl steroid, there is produced the corresponding 21,21-diacylate. Thus, by reacting A 3,11,20 triketo pregnene 21 aldehyde with an excess of acetic anhydride, there is produced the corresponding A -21,21- di'acetoxy,3 ,1 1,20-triketo-pregnene.

The following examples disclose specific applications of i this invention and are included to illustrate but not limit the invention. i p

i EXAMPLEI Production of A? 3,11,20 {triketo 17a hydroxypreg nene 21 --aldehyde A hot solution of 6.0 of .eupric acetate hydrate in 200ml. of methanol containing 1 ml.,of glacial acetic cupric acetate in a suitable solvent such as water or a polar organic solvent. Examples of suitable polar organic solvents for this purpose are the lower alcohols, acetone, dioxane,'tetrahydro furan, and dimethoxyethane. 'Generally,'it is found'that maximum yields of the desired 17- glyoxyl steroid are obtained under optimum conditions by eifecting the reaction at an acid pH. This is accomplished by adding a minor amount of an acid such as "acetic acid to the reaction mixture.

. mixture.

factory since it is long, requiring three separate reactions,

and results in poor yields of the 17-g1yoxyl steroids.

Therefore, one object of this invention is to provide a novelone-step process for producing 17-glyoxyl steroids from 20-keto-21-hydroxy steroids. A further object is to provide novel 17-glyoxyl steroids and aldehyde addition products thereof. Other objects will be apparent from the detailed description hereinafter provided.

According to the present invention it has been found that 17-glyoxyl steroids can be produced by a direct, one step process which comprises reacting the corresponding 20-keto-21-hydroxy steroid with cupric acetate. This process may be conveniently illustrated as follows:

The production of the 17-glyoxyl steroids ispreferably effected by reacting about two equivalents of cupric acetate with one equivalent of a '20-keto-21-hydroxy steroid. The use of a slight excess of cupric acetate, such as 2.1 to 2.2 equivalents thereof, serves to produce the best yields of the aldehydes. V p

The reaction is most conveniently achieved by intimately contacting the 2 0 keto 21 hydroxy steroid and 20 diketo 115 hydroxypregnene 1, -,aldehyde, A 3,2'0 diketopregnene 21 aldehyde, 3,20 a diketopregnane 21 aldehyde and A 3,20 diketo 1701- hydroxypregnene 21 aldehyde.

The novel 17-glyoxyl steroids of this invention may be converted to useful aldehyde addition products, such as cyanohydrins, hemiacetals, hemimercaptals, 'acetals, and mercaptals according to conventional methods. Thus, bisulfite addition products may be conveniently produced by reacting a 17-glyoxyl steroid with an aqueous solution of a suitable alkali metal or alkaline earth metal bisulfite. In addition, hemiacetals and acetals are readily produced r The reaction proceeds slowly at normal temperatures but may be more quickly accomplished at elevated temperatures, preferably reflux temperature of the solvent At 'the reflux temperature the reaction is usually complete within an'hour. After the reaction has been completed, the 17-glyoxyl steroid may be readily separated from the reaction mixture by conventional methods One such .typical separation method comprises filtering the reaction mixture to remove cuprous oxide and adding water to the filtrate to precipitate'the product. The 17- glyoxyl steroids are ordinarily recovered as hydrates but yield the free aldehydes :after drying under suitable conditions. I 1

The 20-keto-21-hydroxysteroids which are convertible by this process to the corresponding 21-aldehydes may be saturated or unsaturated and substituted or unsubstituted. Thus, the steroid nucleus maybe unsaturated such as at the 4:5, 7:8, 9:11, and 11:12 positions. In addition, nuclear substituents may be present in the steroid structure such as keto groups at the 3 and 11 positions, hydroxy groups at the 3, 11 and 17 positions, and halogen substituents at the 2, 4, 6, and 12 positions. Representative of such 20-keto-21-hydroxy steroids which may be converted to the corresponding 21-aldehydes and hydrates thereof by this invention are A? -.3,l1,20 triketo 170:,21

dihydroxypregnene- (cortisone), At- 3,20 diketo 11B,17a,21 trihydroxypregnene (hydrocortisone), 3,11,- 20 triketo 1711,21 -.dihydroxypregnane v(dihydrocortisome), 3,20 diketo llfi,17u,2l trihydroxypregnane (dihydrohydrocortisone), 3,11,20 triketo 1701,21 dihydroxyallopregnane ,(allodihydrocortisone), 3,20 diketo 1l5,17a,21 trihydroxyallopregnane v(allodihydrohydrocortisone), A' 3,11,20 triketo 21 hydroxypregnene (11 dehydrocorticosterone), A 3,20 diketo 115,21 dihydroxypregnene (corticosterone), A? -.3,20 diketo,- 21 hyd-roxypregnene (desoxycorticosterone), 3,20 diketo 21 hydroxypregnene (dihydrodesoxycorticosterone) and A 3,20- diketo 1701,21 dihydroxypregnene (17 hydroxydesoxycorticosterone).

Examples'of some l7-glyoxyl steroids which can be produced from the corresponding 20-keto-21-hydroxy steroids by the application of this invention are A -3,1l,-

2O triketo 17a hydroxypregnene 21 aldehyde, A 3,20 diketo 113,17 dihydroxypregnene 21- aldehyde, 3.11.2.0 triketo 17c hydroxypregnane 21- aldehyde, 3,20 diketo 1118 17cc dihydroxypregnane- 2 1 aldehyde, 3,11,20 triketo 17a hydroxy-allopregnane ZI aldehyde; 3,20 diketov 11B 17a dihxy droxyallopregnane 21 aldehyde, A l 3.11.20 triketo pregnene 21 aldehyde, A 3, acid was added to a hot solution of 5.0 gm. of A 3.11.20 triketo- 170;,21- dihydroxypregnene in 200 m1. of methanol. The mixture was then refluxed for 30 minutes during which time cuprous oxide precipitated. About 75 ml. of water was added to the mixture and refluxing continued for minutes. The mixture was filtered, 25 ml. of water was added to the filtrate, and the mixture concentrated under reduced pressure to about 75 ml. Then .50 mhot water was added, and the solution was concentrated to 75 m]. A 3,11,20 triketo 17a hydroxypregnene 21 aldehyde crystallized from solution as a monohydrate. After coolingthe reaction mixture in an ice bath, the product was collected and washed with water. The product gave an aldehyde test with Fuchsin aldehyde reagent and formed a quinoxaline with O-phenylenedia -mine. By reacting the product in methanolic solution with an equivalent amount'of an aqueous solution of sodium bisulfite, the corresponding sodium bisulfite addition product of A 3,11,20 triketo 17a hydroxypregnene 2'1 aldehyde was prepared;

EXAMPLE .2

Production of A 3,20 diketo 11fi,17oc dihydroxypregnene 21 aldehyde A hot solution .of 6.0 gm. of cupric acetate hydrate in 200 ml. of methanol containing 1 ml. of glacial acetic acid was added to a hot solution of 5.0 gm. of r -3,20- diketo 1lfi,l70c,21 .trihydroxypregnene in 200 mL of methanol. The reaction mixture was refluxed for 30 minutes, '75 ml. of water was added, and refluxing continued for one hour during which time cuprous oxide precipitated. The reaction mixture containing A--3,20- diketo 11 3,1711 dihydroxypregnene 21 aldehyde was filtered and the filtrate concentrated under reduced pressure to an :oil. The yellow oil was dissolved in hot acetone and water was added until a cloud formed. The

solution was clarified with charcoal and the acetone removed under reduced pressure. A 3,20 diketo 11,3,- 170; dihydroxyp-regne-ne '21 aldehyde precipitated from solution as a monohydrate and was collected by filtration. 'It gave an aldehyde reaction with Fuchsin aldeh-yde reagent.

EXAMPLE 3 Production of A -.3.,1LZQ-triketopregnene-Zl -aldelzyde To a solution of 200 mg. of A -3,11,'2-0-triket0-21- hydroxypregnene in-10 ml. of methanol containing 3 drops of glacial aceticacid was added a solution of 240 mg. of cupric acetate hydrate in 30 ml. of methanol. The mixture-was refluxed for minutes and then filtered toremove the cuprous oxide which formed. About 4on1. of water was added to the methanolic solution of A 3,11,20 triketopregnene 21 aldehyde and the mixture concentrated under reduced pressure to about 10 ml. The product crystallized from solution as a monohydrate and was recovered by filtration and dried.

EXAMPLE 4' Production of 3,11,20 'lriketo 17a hydroxy'pregnane- 21 -aldehyde 7 .A solutionof .500 mg. of 3,11,20-triketo-17a,21-dihydroxypregiiane in 20 ml. of methanol containing 5 drops of glacial acetic acid was combined with a solution of 540 mg. of cupric acetate hydrate in ml. of

methanol. The mixture was refluxed for 45 minutes and filtered to remove the cuprous oxide which formed. The filtrate containing 3,11,20 triketo 17a hydroxypregnane 21 aldehyde was diluted with 50 ml. of Water and concentrated under reduced pressure to about 20 ml. The product crystallized from solution as the monohydrate and was recovered by filtration and washed with water.

Various. changes and modifications in the procedures herein disclosed will occur to those skilled in the art, and to the extent that such changes and modifications are embraced by the appended claims, it is to be understood that they constitute part of my invention.

What is claimed is:'

1. The method of producing a M-pregnene-Zl-aldchyde having the formula wherein R and R represent substituents from the group consisting of hydrogen, hydroxy, keto, lower alkoxy, and lower acyloxy radicals, .and R" represents a substituent from the group consisting of hydrogen, hydroxy and lower .acyloxy radicals, which comprises reacting the corresponding A 2O keto 21 hydroxypregnene with cupric acetate.

2. The method of producing A 3,11,20 triketo- 17a hydroxypregnene 21 aldehyde which comprises reacting-A 3,11,20 t-riketo 17a,21 dihydroxypregnene with cupricacetate.

3. The method of producing M 3,20 diketo 11a,- 17a dihydroxypregnene 21 aldehyde which comprises reacting A 3,20 diketo 11fl,-17a,21 trihydroxypregnene with .cupric acetate. I a 4. A process which comprises reacting a 11,2l-dihydroxy .20 keto pregnane with cupric acetate to produce the corresponding 11 hydroxy 17 glyoxylpregnane.

5. A process which comprises reacting a A 20 ketoll,21 dihydroxypregnene with cupric acetate to produce the corresponding A 4 20 keto 11 hydroxypregncne 21 aldehyde.

-References Cited in the file of this patent UNITED STATES PATENTS 2,265 ,488

Miescher a Dec. 9, 1941 2,275,790 Mieseher Mar. 10, 1942 2,322,809 'Logemann June 29, 1943 2,684,376 Oliveto July 20, 1954 OTHER REFERENCES Rogers: JourQAm. Chem. Soc. 74, page 2947, June 5, 1952 (received date May 19, 1952'). 

6. A PROCESS WHICH COMPRISES REACTING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 20 - KETO - 21HYDROXYPREGNENES, 20 - KETO - 21 - HYDROXY - ALLOPREGNANES AND 20 - KETO - 21 - HYDROXYPREGNANES WITH CUPRIC ACETATE TO PRODUCE THE CORRESPONDING 20 - KETO - 21 - ALDEHYDE COMPOUND. 